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Update: Analysis of L-Tryptophan for the Etiology of Eosinophilia-Myalgia Syndrome

In August 1990, CDC and the Food and Drug Administration proposed a structure for peak 97 (Figure 1A), the high performance liquid chromatographic (HPLC) peak that was most predictive of L-tryptophan (LT) lots associated with eosinophilia-myalgia syndrome (EMS) cases( 1). This report updates those findings.

Analyses of the product of LT and acetaldehyde show that the product is the di-L-tryptophan aminal of acetaldehyde (DTAA), with the methine bridge coupling the two tryptophan molecules across the indolenitrogens (Figure 1B) rather than the amino nitrogens (Figure 1A). This synthesized product has the same proton nuclear magnetic resonance (NMR) spectra, mass spectra, and HPLC chromatographic properties as peak 97. Key information to support the location of the methine bridgewas provided by the analyses of synthesized product using a two-dimensional long-range 13C-1H shift correlation NMR spectroscopic experiment (2), which demonstrated that the methine proton of the acetaldehyde residue is coupled to carbons 2 and 2' of the LT groups and that protons 2 and 2' of these groups are correspondingly spin-coupled to the methine carbon of the acetaldehyde residue. This experiment could not be performed on the limited quantity of peak 97 collected from the case-associated lots. In addition, chemical derivatization experiments with the synthesized material and with model compounds are consistent with Figure 1B but not with 1A. Reported by: Center for Food Safety and Applied Nutrition, Food and Drug Administration. Center for Environmental Health and Injury Control, CDC.

Editorial Note

Editorial Note: This confirmation of the structure of peak 97 as the DTAA shown in Figure 1B will enable testing of the correct compound for its biologic effects and assessment of any structure-activity relationship. Studies of the biologic effects of synthesized DTAA--including evaluation of the recently developed rat model for EMS(3)--are in progress. Clarification regarding the role of peak 97 may be important in understanding the pathophysiology of EMS and similar diseases (e.g.,toxic-oil syndrome).

References

  1. CDC. Analysis of L-tryptophan for the etiology of eosinophilia-myalgia syndrome. MMWR 1990;39:589-91.

  2. Reynolds WF, McClean S, Perpick-Dumont M, Enriquez RG.Improved 13C-1H shift correlation spectra for indirectly bonded carbons and hydrogens: the FLOCK sequence. Magn ResonChem 1989;27:162-9.

  3. Crofford LJ, Rader JI, Dalakas MC, et al. L-Tryptophan implicated in human eosinophilia-myalgia syndrome causes fasciitis and perimyositis in the Lewis rat. JClin Invest 1990;86:1757-63.

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